Malik, Abdul; (2018) An investigation into the protection of human muscle from hypoxia-reoxygenation injury: Studies using isolated atrial trabeculae obtained from human right atrial appendage harvested during cardiac surgery. Masters thesis (M.D(Res)), UCL (University College London).

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Abstract

Ischaemic heart disease remains the leading cause of death worldwide and its major manifestation is through an acute myocardial infarction (AMI). This usually presents as an ST segment elevation myocardial infarction (STEMI), where an acute plaque rupture leads to a thrombotic occlusion of the coronary artery rendering the myocardium ischaemic that eventually leads to cell death. The most effective strategy of treating this is via percutaneous coronary intervention (PCI) whereby the thrombus is aspirated and stent is implanted within the narrowed segment of the artery. Other treatment options include thrombolysis or emergent coronary artery bypass grafting (CABG) surgery. Although reperfusion is a prerequisite for myocardial salvage, the process itself is capable of inducing cell death in addition to that caused by myocardial ischaemia - a process termed ‘lethal reperfusion injury’. New treatment strategies are required to protect the heart against the detrimental effects of acute ischaemia-reperfusion injury (IRI). Stromal cell-derived factor 1α (SDF-1α or CXCL12), acting through its cognate receptor on target cell membranes has been recognised and demonstrated in animal models to limit myocardial infarction size ollowing acute ischaemia reperfusion injury. We have already established that SDF-1α is an important humoral factor mediating the effects of remote ischaemic conditioning (RIC) such as reducing infarction size in a rat in vivo model as well as improving functional recovery of rat cardiac papillary muscle in an ex vivo model. Whether, SDF-1α can protect human heart tissue is not known, and is investigated here using isolated human atrial trabeculae exposed to simulated IRI. A human atrial trabecular model utilising simulated ischaemiareperfusion injury was used to reiterate the existence of ischaemic preconditioning in human tissue. The model was characterised using various stabilisation, simulated ischaemia and reperfusion times and the challenges encountered with this model are discussed. Human atrial trabeculae obtained during elective cardiac surgery were suspended in organ baths and superfused with modified Tyrode’s solution. Using the optimum stabilisation, simulated ischaemia and reperfusion times, these trabeculae were then subjected to an ischaemic insult. Some of these were preceded by a preconditioning protocol whilst others were pretreated with SDF-1α prior to the simulated ischaemic insult. The end point for the human model was the functional recovery of myocardial contractility. Unlike previous experiments, the trabeculae were stretched to the peak of the Frank- Starling curve prior to assignment to various protocols. The effect of reduced number of stretches is also compared to multiple stretches. The results of this study demonstrate that (a) ischaemic preconditioning is effective in a human model despite evolution of advancing medical therapy, (b) contrary to earlier data, I was unable to demonstrate that stretch caused preconditioning of the human myocardium, (c) SDF-1α act as a preconditioning mimetic and protects it from lethal reperfusion injury and (d) the protection appears to be mediated through its cognate CXCR4 receptors and at least partly via activation of intracellular kinases such as extracellular signal-regulated kinases (ERK). In summary, despite advances in therapy, myocardial infarction is associated with considerable morbidity and mortality. The present study demonstrates the ability of SDF-1α to protect the human atrial tissue and may involve the RISK pathway akin to all forms of conditioning.

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